Massive small bowel resection (SBR) is required therapy for multiple medical and surgical conditions. Intestinal adaptation following SBR is an important compensatory response consisting of mucosal hypertrophy and hyperplasia whit increased bowel caliber, length and thickness. This mitogenic response enhances absorptive and digestive capacity. While it is accepted that adaptation after SBR results in increased cellular proliferation, its effect on programmed cell death (apoptosis) has not been fully elucidated. The experiments described in this application will test the hypothesis that enterocyte apoptosis is increased following small bowel resection and that by retarding apoptosis, the adaptive response of the intestine may be augmented. To this hypothesis, three specific aims are proposed. In the first aim, w will test the hypothesis that enterocyte apoptosis increases during adaptation. Rates of apoptosis and proliferation will be quantified in the ileum during adaptation as well as the expression of apoptosis-associated proteins. The second aim will test the hypothesis that the balance of apoptosis and proliferation is altered during conditions of enhanced (EGF administration) or inhibited (waved-2 mice) adaptation. Rates of apoptosis and proliferation and expression of apoptosis-associated proteins will be measured under these conditions. The third aim will delineate a mechanism for apoptosis-associated proteins will measured under these condition. The third aim will delineate a mechanism for apoptosis during adaptation by testing the hypothesis that the expression of specific proteins are required for apoptosis to occur during adaptation. Transgenic and knockout mice will undergo SBR to determine the impact of specific proto-oncogenes involved during apoptosis. The long-term goals of this application will be to enhance our understanding of intestinal adaptation. By augmenting this response, the requirements and associated morbidity with parenteral nutrition will be reduced.